Inhaled streptokinase vs heparin in ARDS

Accepted Manuscript

Streptokinase versus Unfractionated Heparin Nebulization in Patients

with Severe Acute Respiratory Distress Syndrome (ARDS): A
Randomized Controlled Trial with Observational Controls

Ahmed Abdelaal Ahmed Mahmoud MD, EDAIC, FCAI ,

Hatem Elmoutaz Mahmoud MD , Mohamed Ali Mahran MD ,
Marwa Khaled M.Sc.

PII: S1053-0770(19)30498-7
DOI: https://doi.org/10.1053/j.jvca.2019.05.035
Reference: YJCAN 5303

To appear in: Journal of Cardiothoracic and Vascular Anesthesia

Please cite this article as: Ahmed Abdelaal Ahmed Mahmoud MD, EDAIC, FCAI ,
Hatem Elmoutaz Mahmoud MD , Mohamed Ali Mahran MD , Marwa Khaled M.Sc. , Streptokinase
versus Unfractionated Heparin Nebulization in Patients with Severe Acute Respiratory Distress Syn-
drome (ARDS): A Randomized Controlled Trial with Observational Controls, Journal of Cardiothoracic
and Vascular Anesthesia (2019), doi: https://doi.org/10.1053/j.jvca.2019.05.035

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 ACCEPTED MANUSCRIPT

Streptokinase versus Unfractionated Heparin Nebulization in Patients with Severe Acute

Respiratory Distress Syndrome (ARDS): A Randomized Controlled Trial with

Observational Controls

Short title: Inhaled streptokinase vs heparin in ARDS

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Authors:

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Ahmed Abdelaal Ahmed Mahmoud.1,2 MD, EDAIC, FCAI

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Hatem Elmoutaz Mahmoud.1 MD

Mohamed Ali Mahran.3 MD

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Marwa Khaled.4 M.Sc.

Authors affiliations:
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1: Associate Professor of Anaesthesia, Faculty of Medicine, Beni-Suef University

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2: Department of Anaesthesia, Pain Medicine and Critical Care, Tallaght University Hospital,

Dublin, Ireland.
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3: Lecturer of Anesthesia Faculty of Medicine, Beni-Suef University

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4: Assistant Lecturer of Anesthesia, Faculty of Medicine, Beni-Suef University

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Conflict of interest:

All authors declare no conflict of interest

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Corresponding author:

Ahmed Abdelaal Ahmed Mahmoud MBBCH, MD, EDAIC, FCAI

Associate Professor of Anesthesia Faculty of Medicine, Beni-Suef University.

Department of Anesthesia, Beni-Suef University Hospital

Department of Anaesthesia, Pain Medicine and Critical Care, Tallaght University Hospital,

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Dublin, Ireland.

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ORCID ID: https://orcid.org/0000-0002-0473-9764

Email: carnitin7@yahoo.com

Phone: +353892117836 US
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Address: Department of Anesthesia, Faculty of Medicine, Beni-Suef University Hospital, Beni

Suef, Egypt. P.O. 62511

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Trial registration:
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The trial is retrospectively registered at ClinicalTrials.gov. Trial ID: NCT03465085

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Email Addresses for Authors:

Ahmed Abdelaal Ahmed Mahmoud: carnitin7@yahoo.com

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Hatem Elmoutaz Mahmoud: helmoutaz@gmail.com

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Mohamed Ali Mahran: mali7511@yahoo.com

Marwa Khaled: dr.marwakhaled86@gmail.com

Ethics approval and consent to participate: The study and recruitment were started only

after obtaining approval from the Research and Ethics Committee (Faculty of Medicine, Beni-

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Suef University). A written informed consent was obtained from the guardian, or the first of kin

of the patients participated in the study.

*Consent for publication: Not Applicable

*Availability of data and material: Available upon request

*Competing interests: No competing interest declared by any of the authors

*Funding: The resources of Beni-Suef University Hospital. No other funding sources to be

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declared

*Authors' contributions:

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A.A.A.M.: Invention of the idea, design of the study, writing the final Manuscript.

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M.K.: Application for ethical committee approval, recruitment of patients, clinical work, data
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collection and analysis.

H.E.: supervision of the clinical work, data collection, writing the initial manuscript
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M.A.M.: supervision of the clinical work, data collection, writing the initial manuscript
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*Acknowledgements

We acknowledge Professor Mahmoud Moustafa Amer, the former Head of the Department of
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Anesthesia at Beni-Suef University Hospital for his support while carrying out this research
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Abstract

Objective

To examine and compare nebulizing Heparin versus Streptokinase on reversing alveolar

collapse non-responsive to recruitment.

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Design

A clinical trial at a tertiary intensive care unit (ICU). Sixty patients with severe acute

respiratory distress syndrome (ARDS) (PaO2/FiO2<100) non-responsive to recruitment

maneuver (RM), prone position (PP) and neuromuscular block (NMB) were randomized into

intervention arms or standard-of-care arm.

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Setting

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ICU at Beni-Suef University Hospital

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Participants

Sixty patients with severe ARDS (PaO2/FiO2<100) non-responsive to RM, PP and NMB.

Interventions US
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Nebulized Heparin (10,000 IU/4 hours), nebulized Streptokinase (250,000 IU/4 hours), and

conservative management.
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Measurements and Main Results

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The primary outcome was the change in PaO2/FiO2; the secondary outcomes included the

change in compliance, plateau pressure, coagulation, and ICU mortality. PaO2/FiO2 was
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significantly higher in Streptokinase group from day 1 to day 8 compared to Heparin and

standard-of-care groups. Streptokinase produced PaO2/FiO2>100 at day 1, >200 at day 5 and

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>300 at day 7. Heparin group achieved PaO2/FiO2>100 at day 5 but remained <200 till day 8.
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The standard-of-care group did not achieve a PaO2/FiO2>100 after 8 days. Streptokinase

significantly reduced plateau pressure and improved compliance at day eight. Only

Streptokinase decreased PaCO2 (P<0.0001). Moreover, ICU mortality was significantly

lower in Streptokinase patients compared to other groups. Additionally, no heparin-

induced thrombocytopenia was observed in all groups.

Conclusion

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Inhaled Streptokinase serves as rescue therapy in patients with severe ARDS with

improving oxygenation and lung mechanics more quickly than heparin or conventional

management.

Keywords: ARDS, Streptokinase, Heparin, Nebulization, Inhaled Thrombolytic Therapy,

Inhaled Anticoagulation.

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The trial is retrospectively registered at ClinicalTrials.gov. Trial ID: NCT03465085

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Introduction:
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Severe hypoxemia and multiple organ failures are features that present in severe Acute
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1
Respiratory Distress Syndrome (ARDS) with an inability to recruit the widespread collapsed
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alveoli in these patients. The resistance of the collapsed alveoli to trials of recruitment

maneuvers (RM) is attributed mainly to intra-alveolar clot formation secondary to intra-

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3-10
alveolar fibrin deposition due to alveolar capillary injury and leakage. Additionally, ARDS

is associated with an inflammatory process that enhances clot formation and inhibits
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fibrinolysis in the injured lung units, while in the non-injured lung, low levels of tissue
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plasminogen activator inhibitor-1 prevent fibrin accumulation. 3

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A broad spectrum of treatments has been examined to manage ARDS including
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interventions to stimulate fibrinolysis or block coagulation to suppress the inflammatory

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response and reduce lung injury. Various experimental studies have explored the use of

profibrinolytic agents. ARDS patients treated with nebulized Urokinase or Streptokinase

showed improved PaO2/FiO2, without bleedings or significant changes in the clotting

mechanism. 13-15

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Streptokinase has no proteolytic activity by itself, however, it indirectly activates

human plasminogen to plasmin by first forming a high-affinity equimolar complex with

plasminogen, which is not affected by α2- antiplasmin. 16

The Heparin anticoagulant effect is mainly mediated through its interaction with anti-

thrombin III (ATIII); this produces a conformational change in ATIII which markedly

accelerates the ability of Heparin to inactivate thrombin, factor Xa, and factor IXa, with

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thrombin being the most sensitive to inhibition by Heparin/ATIII. 17

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Failure of current management approaches in patients with ARDS are of a great concern

for researchers such as RM with high rates of complications such as respiratory desaturation,

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hypotension, transient circulatory depression, new air leak in both young and old patients18,

prone position (PP), a complicated approach that takes an entire team to accomplish, and some
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patients may be critically ill during the therapy, or neuro-muscular block (NMB) whereas

hypoxemic patients often need a prolonged use of NMB, hence there are neuromuscular
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dysfunction and weakness resulting in more ventilation days, and hospital stay, as well as
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19, 20
prolonged rehabilitation. Thus, new strategies are needed as a rescue treatment in patients

with ARDS. Hence, the current trial 21 represents the first study aiming to assess the role of the
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nebulized thrombolytic agent, Streptokinase, and the nebulized anticoagulant Unfractionated

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Heparin on reversing alveolar collapse in patients with severe ARDS.

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Methods

Ethical Statement

The study was carried out from March 2016 to January 2018 in the intensive care unit

(ICU) of a tertiary University Hospital following approval by the local Research and Ethics

Committee. Written informed consent from the first of kin of the recruited patients was obtained.

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First of kin consent was required due to the inability of intubated and sedated patients to consent

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for themselves. Moreover, all the methods were conducted in accordance with the relevant

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approved regulations, guidelines, and declaration of Helsinki. The trial was registered after the

completion of recruitment at clinicaltrials.gov (NCT03465085).

Eligibility and Randomization US

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Adult patients aged 21-60 years admitted to our ICU with the diagnosis of ARDS
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according to Berlin definition were eligible if the following inclusion criteria were fulfilled:
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23 24 25
severe ARDS with PO2/FiO2<100; failure of RM , PP or NMB to improve hypoxemia;

completed ten days of standard-of-care (SOC), including intubation and ventilation; no

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contraindications to thrombolytic or anticoagulant therapy (e.g. coagulopathy, heparin-induced

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thrombocytopenia, previous administration of streptokinase, known or suspected allergy to

heparin or streptokinase, intracranial hemorrhage in the past 12 months, an epidural catheter in

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place or likely to be placed within the following 48 hours, static compliance>50 ml/cmH2O; and

no immunosuppression). All patients received antibiotics as necessary per culture and sensitivity
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results.

Randomization to either Heparin or Streptokinase groups was applied to patients whom

first of kin agreed to participate in the trial. A random set of numbers were generated

(www.randomizer.org). Each number was sealed in an opaque envelope and kept in the ICU.

One envelope was randomly selected after a patient was enrolled. The key for assigning numbers

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to either group was stored on an encrypted USB device with one of the investigators.

Furthermore, one of the investigators was responsible for preparing the medication nebulizer

while the nurse and the ICU physician attending the case and recording the data were blinded to

the patient’s group. Preparations were stored in ICU at 2-8 °C. Patients of whom first of kin

declined to participate were followed as a SOC group, with written informed consent to use their

data and another approval from the local Research and Ethics Committee.

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Intervention

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The Heparin group received inhaled Unfractionated Heparin at a dose of 10,000 IU/4

hours by a nebulizer, with the total daily dose of nebulized Unfractionated Heparin 60,000 IU.

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Indeed, the selected the unfractionated heparin dose defined as "the high dose" in a meta-analysis

on heparin nebulization in ARDS 26 and was similar to that used by Miller et al. 27
However, our
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Heparin dose was lower than the doses used by Dixon et al. (400,000 IU/day and 150,000 IU/day

in two studies 28, 29).

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Moreover, the Streptokinase group received Streptokinase at a dose of 250,000 IU/4

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hours by a nebulizer, with a total daily dose of nebulized Streptokinase of 1,500,000 IU. It is

noteworthy that we were guided in selecting the nebulized streptokinase dose by the maintenance
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intravenous dose of Streptokinase in ARDS applied in a previous trial , where the dose was
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60,000 U/kg bolus followed by 15,000 U/kg/hour for a mean of 60 hours (total 24 hours

systemic Streptokinase of 1,500,000 U for 100 kg patient). In addition to that, it has been known
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that proteins can be absorbed from the lung where macromolecules <40 kDa (<5–6 nm in

diameter) rapidly appear in the blood following inhalation into the airways, as demonstrated with

insulin 30 appearing in blood 15–60 minutes post- inhalation 31-33 while macromolecules >40 kDa

are slowly absorbed over many hours such as Streptokinase 34 which leads to a slow and gradual

absorption via the alveoli, thus it serves its effect in severe ARDS and severe hypoxemia.

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All patients received the routine intensive care protocol for cases of ARDS including the

specific ventilatory protocol 35 with monitoring and recording of PaO2 [arterial partial pressure of

oxygen], FiO2 [fraction of inspired oxygen], PaO2/FiO2, lung compliance [ml/cmH2o], peak

airway pressure [cmH2o], bleeding profile [platelets count, prothrombin concentration,

International Normalized Ratio, and bleeding time] and any complications as bleeding,

coagulopathy, heparin-induced thrombocytopenia, and allergic reactions.

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36, 37
Indeed, nebulized heparin and streptokinase are well-absorbed through pulmonary

capillary membrane since the lung is preferred for its features such as a large absorption area,

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38, 39
extensive vascularization of the respiratory mucosa, and a low enzymatic activity .

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Moreover, it has been demonstrated to be effective locally in treating diseases, such as acute lung

injury (ALI) 40, 41, pulmonary embolism 42, 43, asthma 44, 45, and cystic fibrosis 46, 47.
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The potential of airways and alveoli to absorb particles and chemical substances is

impressive. The layer of liquid and surfactant covering the epithelial cells is continuous and
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offers relatively uniform diffusion possibilities. Inhaled particles can be observed submersed in
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the aqueous lining layer and adjacent to epithelial cells 48. This allows interaction with these cells

as well as diffusion through them into interstitial space and vascular and alveolar structures.
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Start and Termination of Therapy

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Heparin nebulizer or Streptokinase nebulizer continued until the occurrence of one or

more of the following: PaO2/FiO2>300; improved compliance (static compliance>50

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ml/cmH2O); the occurrence of complications; failure of the therapy to produce improvement in

hypoxemia or compliance after 72 hours. In the case of improvement in oxygenation or

compliance, therapy continued for a maximum of four days.

Nebulization and Ventilation: (Supplements 1A, 1B, and 1C)

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To ensure adequate drug delivery, the ventilatory settings were changed to a volume-

controlled ventilation with TV 500 ml, respiratory rate (RR) 14/minutes, I:E ratio of 1:1.5,

inspiratory pause 75% of the inspiratory time, PEEP 10 cmH2O with FiO2 of 1.

Plateau pressure limit up to 30 cmH2o, and CO2 was maintained within the normal limit

(35-45 mmHg), PEEP was maintained 10 mmHg; the RR was adjusted according to CO2 level

and I:E ratio was maintained at 1:2.

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Extubation was considered if patients meet the criteria of weaning such as being

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hemodynamically stable and cooperative in addition to minimal ventilator parameter (SpO 2>95%

on a pressure support mode <10 cm H2O, PEEP <5 cm H2O and FiO2 <50%). We adjusted FiO2

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and PEEP to maintain PaO2 55–80 mmHg through using PEEP 8-12 cmH2O if PaO2/FIO2 ≥250

and PEEP>12 cmH2O if PaO2/FiO2 <250. Moreover, the potential for lung recruitment can be
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identified by the use of a 30 minutes trial of increase PEEP at 15 cmH 2O.
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In addition, we used PCV with driving pressure 20-25 cmH2O with PEEP 20-25

cmH2O, RR 10/min, I: E 1:1, FiO2 for 2 minutes and PCV with a stepwise increase in PEEP
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every 2 minutes, keeping the driving pressure constant up to PIP of 40-50 cmH2O. It is

noteworthy as well that we determined the optimal PEEP using the decremental PEEP
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technique. Furthermore, CPAP 30-50 cmH2O for 20-40 seconds with PCV with driving
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pressure 20-25 cmH2O with PEEP 20-25 cmH2O, RR 10/minutes, I: E 1:1, FIO2 for 2 minutes

and PCV with a stepwise increase in PEEP every 2 minutes, keeping the driving pressure
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constant up to PIP of 40-50 cmH2O.

Outcomes

The primary outcome was the mean daily ratio of PaO2 to FiO2 (PaO2/FiO2). Moreover,

secondary outcomes included static compliance, plateau pressure, change in PaCO2, ventilator-

off days (patient using the spontaneous ventilation only) in surviving patients at ICU discharge,

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ICU mortality at discharge from ICU, and bleeding profile (including platelets count,

prothrombin concentration, INR, bleeding time, and APTT) and occurrence of any bleeding

complications, or heparin-induced thrombocytopenia, and blood transfusion.

Sample size estimation and Statistical analysis

The sample size was calculated after obtaining preliminary data from five patients

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receiving SOC with a mean PaO2/FiO2 of 82 at day eight (SD=13). 35 Assuming 30% difference

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between groups to reflect a moderate effect size, 95% power, alpha=0.05, and doubling SD, the

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total sample size was 57 patients, increased to 60 for attrition (G power software version 3.1.3,

Düsseldorf, Germany).

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The data were examined for normality using the skewness and Kurtosis tests. Continuous
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variables are expressed as mean±SD (or median and inter-quartile range (IQR), as appropriate)

and were compared for differences between groups using independent t-tests. Paired t-tests were
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used for intragroup comparisons from day one to day eight, separately for each group. Mixed-

design analysis of variance tested the effect of group, time, and group×time interaction.
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Categorical variables were compared using Chi-squared tests or Fisher’s exact tests, as

appropriate. For all comparisons, P<0.05 is considered significant. IBM SPSS Advanced
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Statistics Version 22.0 was used for data analysis (SPSS Inc., Chicago, IL).
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Results

Within the study period, our ICU received 1,796 admissions, 636 (35.4%) of which were
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diagnosed as ARDS. However, 314 of those (49.37%) were diagnosed as severe ARDS

(PaO2/FiO2<100). Sixty patients met inclusion criteria and were recruited to the trial after the

failure of RM, PP and NMB (PaO2/FiO2 persistently<100). Twenty were allocated as a SOC

group after the guardian’s decline to participate but consent to use their data. The remaining

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patients were randomized equally to Heparin group (n=20) or Streptokinase group (n=20),

(Figure 1).

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The groups were well-matched on age, gender, weight, height, Glasgow coma scale (GCS),

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“acute physiology, age, chronic health evaluation II” (APACHE) II score, sequential organ

failure assessment (SOFA) score, and cause of ARDS (all Ps>0.05). Sepsis was the most
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common cause of ARDS in the three groups, 14 (70%) in Heparin group, 16 (80%) in

Streptokinase group and 17 (85%) in the SOC group. Multiple trauma was the second most
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common cause of ARDS in all groups (Supplement 2).

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PaO2/FiO2: (Supplement 3 and Figure 2)

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There was no significant difference between the three groups in baseline PaO 2/FiO2. PaO2/FiO2

was significantly higher in the Streptokinase group on all days (all Ps<0.001). Patients in the
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Heparin group achieved PaO2/FiO2>100 at day five but remained with PaO2/FiO2<200 until day

8. Patients in the Streptokinase group achieved PaO2/FiO2>100 at day one, PaO2/FiO2>200 at

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day five, and PaO2/FiO2>300 at day 7. Patients in the SOC group did not achieve a

PaO2/FiO2>100 after 8 days of conservative management.

Ventilator-free days during ICU stay (Supplement 2)

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Streptokinase patients had more ventilator-free days (median (IQR): 5.57 (2.7) days) than both

the Heparin group (3.11 (3.5) days, P<0.001) and the SOC group (1.2 (1.1) days, P<0.001).

However, the Heparin group had more ventilator-free days than the SOC group (P<0.05).

ICU mortality (Supplement 2)

ICU stay was shorter in Streptokinase patients (median (IQR): 17 (3.5) days) than in both

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Heparin (27.76 (5.5) days, P<0.001) and SOC (33.64 (8.6) days, P<0.001) patients. ICU stay was

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shorter in the Heparin group than in the SOC group (P=0.001).

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ICU mortality was lower in Streptokinase patients (35%) than in both Heparin group (70%,

P=0.027) and SOC group patients (90%, P<0.001). There was no significant difference in ICU

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mortality between the Heparin group and the SOC group (P=0.11). Mortality in the three groups
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happened after the first eight days of the study.

Plateau pressure: (Supplement 4 and Figure 3)

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There was no significant difference between the three groups in the baseline Plateau pressure.
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Plateau pressure was lower in Streptokinase group on all days (all Ps<0.01). The Heparin group

had lower Plateau pressure than the SOC group on day seven only (P=0.01). Plateau pressure in
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the Streptokinase group decreased from 33±1 at day 0 to 17.69± 2.5 cmH2O at day 8 (P<0.001).
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Although the reduction in the plateau pressure from day 0 to day 8 in the Heparin and the SOC

group was statistically significant (P<0.001), neither group achieved a value less than 30 cmH2O
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at day eight (30.3±2.8 in the Heparin group and 31.7±1.7 cmH2O in the SOC group).

Compliance: (Supplement 5 and Figure 4)

There was no significant difference between the three groups in baseline compliance.

Compliance was higher in the Streptokinase group on all days (P<0.001).

The Heparin group was higher in compliance than the SOC group on day eight only (P=0.008).

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Compliance increased more than threefold over eight days among the Streptokinase group (from

19.8±1.6 at day 0 to 68.1± 4.6 cmH2O at day 8 (P<0.001). Although the increase in compliance

from day zero to day eight in the Heparin and the SOC group was statistically significant

(P=0.014 and P=0.02, respectively), neither group achieved a value more than 25 cmH2O at day

8 (25.2±5.69 in the Heparin group and 20.9±16 cmH2O in the SOC group).

PaCO2: (Supplement 6 and Figure 5)

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There was no significant difference between the three groups on baseline PaCO 2. The

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Streptokinase group showed a significant reduction in PaCO 2 compared to the other two groups

at day eight (P<0.001). There was no significant change in PaCO2 in either other groups.

Tracheostomy and extubation: (supplement 7) US

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Coagulation and bleeding profile in intervention groups: (supplement 8 [A-C])
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Discussion:

35
Patients with severe ARDS and resistance to RM, PP, and NMB demonstrated

significant improvements in oxygenation, ventilation, ventilatory parameters and survival rate in

response to nebulized Streptokinase. The marked effects of streptokinase support the previous
9, 10, 15, 49-51
animal and human trials examining the effect of thrombolytics on ARDS models and

patients. Effects are mostly explained by the ability of streptokinase to break down intra-alveolar

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clots, enabling the collapsed alveoli to expand and reversing one of the main pathologies

associated with ARDS. 3, 11-14

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The use of intravenous or nebulized thrombolytics in ARDS has been previously

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examined, based on the proposed pathophysiology of either alveolar capillaries or intra-alveolar

clot formation, respectively, in ARDS. In an animal study by Hardaway et al. 15

plasminogen
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activators were administrated intravenously in a porcine model of ARDS, producing an increase

in arterial oxygenation and providing a survival advantage. Tissue plasminogen activator and
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urokinase plasminogen activator protected against acute lung injury. Other trials by Hardaway et
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al. 9, 10 administered 45,000 units of activated plasminogen intravenously to patients with ARDS,

aiming to unblock the obstructed pulmonary microcirculation by clots as a sequel of

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Disseminated Intravascular Coagulopathy associated with ARDS, displaying a dramatic

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improvement in his studies without significant bleeding complications.

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Hofstra et al. investigated the effect of two pro–fibrinolytic agents and monoclonal
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antibodies against plasminogen activator inhibitor–type 1 (anti–PAI–1) in rat models of direct or

indirect ALI and concluded the nebulized rtPA or anti–PA1–1 affects pulmonary fibrinolysis but
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not inflammation. Gram et al. reported a case where, after combining intravenous and

inhalation thrombolytic therapy in one patient with ARDS and persistent hypoxemia, the patient

developed an adequate improvement.

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Whether intravenous- or nebulizer-administered Streptokinase, previous trials

9, 10, 15, 49-51
demonstrated improvement in pulmonary mechanics and oxygenation. These results

support our findings. Notably, the nebulizer route can be advantageous to avoid the possible

systemic side effects of Streptokinase.

Streptokinase, a glycosylated polypeptide chain consisting of 414 amino acids, has a

molecular weight of 47.3 kDa. Theoretically, slow systemic absorption of Streptokinase through

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the alveoli can take place (by either intracellular or paracellular mechanisms) as seen with

other polypeptide macromolecules such as α1-antitrypsin (45–51 kDa) and albumin (68 kDa)

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34, 53
(Inhaled Tmax of 12-48 and 20 hours, respectively). The possibility of slow and gradual

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absorption of Streptokinase through the alveoli may explain the marked effect of Streptokinase

in severe ARDS and severe hypoxemia. This may be through lysis not only of the intra-alveolar
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clot but also of the alveolar-capillary clot, thus reversing the obstruction of both alveolar

ventilation and perfusion. The absence of coagulopathy seen with inhaled Streptokinase may be
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due to this potential slow systemic absorption, loss of Streptokinase in the breathing circuit and
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the consumption of Streptokinase in dissolving intra-alveolar clots.

Though markedly better than the SOC group, our findings showed that the local
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anticoagulant effect of Heparin failed to reverse the pulmonary pathology and improve
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oxygenation or to improve survival rate as efficiently as Streptokinase. Our results agree with
28, 29
Dixon et al. who found that nebulized heparin did not cause significant changes in the
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PaO2/FiO2. Similarly, Holt et al. failed to demonstrate significant improvement in PaO2/FiO2
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in a group that received heparin 5,000 IU. In contrast to our result, Miller et al. reported a

significant improvement in lung injury score, pulmonary compliance, and hypoxia score in a

patient managed with heparin nebulized every four hours. Murakami et al. 55 found that in sheep,

PaO2/FiO2 markedly decreased with the saline nebulizer, while nebulized heparin, decreased

PaO2/FiO2 significantly after twelve hours.

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The relatively late mild to moderate effect of nebulized Heparin compared to the SOC

group in our study can be due to the action of Heparin on the pulmonary macrophages leading to

attenuation of both inflammation and coagulation. 56, 57

During the nebulization of the medications, we modified the ventilatory parameters into

volume-controlled ventilation with an increase in both the inspiratory time and the inspiratory

pause. Additionally, the nebulizer chamber was situated as near as possible to the endotracheal

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tube to allow the best delivery of the nebulized medication. 58

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According to the aforementioned explanation of the used doses of the two therapies, the

optimal dose has not been established yet, hence we recommend future studies to investigate the

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optimal doses of unfractionated heparin as well as the nebulized streptokinase in ARDS patients.

Moreover, we used off-label drugs in ARDS patients. In fact, off-label prescription use is
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both prevalent and legal (21% of prescribed therapies or an estimated 150 million prescriptions
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in the USA). Physicians cite the absence of medications intended for a particular indication as
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being the primary reason for off-label prescribing. Off-label use of therapies has been studied
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60, 61
as a potential factor to preventable adverse effects of drugs, with the risk for adverse effects

increased by 44% with off-label use compared to on-label use, especially if not supported by
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strong evidence. However, we have clearly discussed above the reasons for using these drugs.
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It is worth mentioning that we had a high rate of ARDS patients in our study. This could

be attributed to conducting the study in a tertiary university hospital with a major trauma center,
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moreover the two major problems causing the increased rate of ARDS were trauma and sepsis
62, 63 64
and Egypt has a high rate of road traffic accidents and a high antimicrobial resistance

which cause severe sepsis and development of severe ARDS in septic patients.

Additionally, we noted a high mortality rate in the control group which may be attributed to the

older age in this group. Similarly, a previous report stated that the increased age was associated

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with higher ICU mortality. 65 Previous studies indicated that the mortality depends on the

geographic location of studies 66 and being in a developing or developed country. Although some
67, 68
studies revealed decreased mortality rates compared to historical control groups , some

studies still report high mortality rates 69-71 whereas the highest mortality rate (88.2%) was found
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in patients having ≥75 years old. On the contrary, the mortality was around 30% in patients

with H1N1 influenza and ARDS treated with ECMO 72. Moreover, the in-hospital mortality rate

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for patients with H1N1-related ARDS was 23.7% for ECMO-referred patients as compared to

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52.5% for non–ECMO-referred patients 73.

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Limitations:

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Our study was a single center study and did not use an imaging investigation such as CT

thorax and lung perfusion scan or a histopathological investigation as broncho-alveolar lavage

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(BAL), which would have added evidence for the pathophysiology and the mechanism of action

of the studied medications. However, CT thorax was not performed to avoid the risk of
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transferring critically-ill patients. Additionally, BAL was not performed to avoid inducing any
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74, 75
possible complications or aggravating hypoxemia in cases with severe ARDS. Moreover,

the sample size might be small to detect any uncommon bleeding events. Besides, we have
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registered the study after completion of recruitment. Notably, we might have a possibility of

selection bias since we used patients who were not enrolled as controls.
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Our study is strengthened by the randomized controlled design with observational control
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cases, an adequate level of blinding and the use of objective parameters for assessment and

comparison.

Conclusion:

The Streptokinase dramatically improved oxygenation, lung mechanics, ventilation,

plateau pressure and compliance with resultant higher extubation rate, shorter ICU stay, as well

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as higher survival rate compared to unfractionated heparin or conventional management in

patients with severe ARDS. Hence, our findings throw the light on using the nebulized

Streptokinase as rescue therapy in patients with severe ARDS non-responsive to RM, PP, and

NMB. The possible mechanism of these effects is the lysis of intra-alveolar clots allowing re-

expansion of collapsed alveoli. Moreover, we did not note any laboratory or clinical

abnormalities in coagulation and the bleeding profile. Further studies on nebulized Streptokinase

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are required to explore its pivotal role in milder types of ARDS. Besides, future studies may

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include imaging techniques such as CT thorax to explain the clinical significance of using

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nebulized Streptokinase in these patients.

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Figure Legends

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Figure 1. Patients Flowchart.

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Figure 2. P/F (PaO2/FiO2) ratio expressed as the mean and standard deviation (SD) in group I

(Heparin group), group II (Streptokinase group) and group III (Standard of care group). PaO2;

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arterial oxygen tension measured in mmHg. FiO2; the fraction of inspired oxygen. D0: The day

of the start of intervention and data was collected two hours before the start of the intervention.

D1: Data collected 24 hours after the start of the intervention.

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Figure 3. Plateau pressure expressed as mean and standard (SD) deviation in group I (Heparin

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group), group II (Streptokinase group) and group III (Standard of care group). Plateau pressure

is measured in cmH2O. Day 0: The day of the start of intervention and data was collected 2
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hours before the start of the intervention. Day 1: Data collected 24 hours after the start of the

intervention.
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Figure 4. Compliance expressed as mean and standard (SD) deviation in group I (Heparin

group), group II (Streptokinase group) and group III (Standard of care group). Compliance is

measured in ml/cmH2O. Day 0: The day of the start of intervention and data was collected 2

hours before the start of the intervention. Day 1: Data collected 24 hours after the start of the

intervention.

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Figure 5. PaCO2 (arterial carbon dioxide tension) expressed as mean and standard (SD)

deviation in group I (Heparin group), group II (Streptokinase group) and group III (Standard of

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care group). PaCO2 is measured in mmHg. Day 0: The day of the start of intervention and data

was collected 2 hours before the start of the intervention. Day 1: Data collected 24 hours after

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the start of the intervention.

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